Preface xi
About the authors xiii
1 Introduction and overview 1
1.1 Use of drugs in disease states 1
1.2 Important definitions and descriptions 2
1.3 Sites of drug administration 4
1.4 Review of ADME processes 5
1.5 Pharmacokinetic models 7
1.6 Rate processes 12
2 Mathematical review 17
2.1 Introduction 17
2.2 A brief history of pharmacokinetics 18
2.3 Hierarchy of algebraic operations 18
2.4 Exponents and logarithms 18
2.5 Variables, constants, and parameters 19
2.6 Significant figures 20
2.7 Units and their manipulation 21
2.8 Slopes, rates, and derivatives 21
2.9 Time expressions 24
2.10 Construction of pharmacokinetic sketches (profiles) 25
3 Intravenous bolus administration (one-compartment model) 29
3.1 Introduction 29
3.2 Useful pharmacokinetic parameters 30
3.3 The apparent volume of distribution (V) 32
3.4 The elimination half life (t1/2) 36
3.5 The elimination rate constant (K or Kel) 38
3.6 Plotting drug concentration versus time 40
3.7 Intravenous bolus administration of drugs: summary 41
3.8 Intravenous bolus administration: monitoring drug in urine 42
3.9 Use of urinary excretion data 43
4 Clearance concepts 55
4.1 Introduction 55
4.2 Clearance definitions 56
4.3 Clearance: rate and concentration 58
4.4 Clearance: tank and faucet analogy 58
4.5 Organ clearance 60
4.6 Physiological approach to clearance 61
4.7 Estimation of systemic clearance 65
4.8 Calculating renal clearance (Clr) and metabolic clearance (clm) 66
4.9 Determination of the area under the plasma concentration versus time curve: application of the trapezoidal rule 67
4.10 Elimination mechanism 69
4.11 Use of creatinine clearance to determine renal function 69
Appendix Recently developed equations for estimating creatinine clearance and glomerular filtration rate 76
Problem set 1 79
5 Drug absorption from the gastrointestinal tract 95
5.1 Gastrointestinal tract 95
5.2 Mechanism of drug absorption 98
5.3 Factors affecting passive drug absorption 100
5.4 pH-partition theory of drug absorption 101
6 Extravascular routes of drug administration 105
6.1 Introduction 106
6.2 Drug remaining to be absorbed, or drug remaining at the site of administration 106
6.3 Determination of elimination half life (t1/2) and elimination rate constant (K or Kel) 109
6.4 Absorption rate constant (Ka) 110
6.5 Wagner-Nelson method (one-compartment model) and Loo-Riegelman method (two-compartment model) 111
6.6 Lag time (t0) 115
6.7 Some important comments on the absorption rate constant 116
6.8 The apparent volume of distribution (V) 116
6.9 Time of maximum drug concentration, peak time (tmax) 117
6.10 Maximum (peak) plasma concentration (Cp)max 118
6.11 Some general comments 120
6.12 Example for extravascular route of drug administration 121
6.13 Flip-flop kinetics 126
Problem set 2 127
7 Bioavailability/bioequivalence 137
7.1 Introduction 138
7.2 Important definitions 138
7.3 Types of bioavailability 139
7.4 Bioequivalence 141
7.5 Factors affecting bioavailability 141
7.6 The first-pass effect (presystemic clearance) 142
7.7 Determination of the area under the plasma concentration-time curve and the cumulative amount of drug eliminated in urine 143
7.8 Methods and criteria for bioavailability testing 145
7.9 Characterizing drug absorption from plasma concentration versus time and from urinary data following the administration of a drug via different extravascular routes and/or dosage forms 155
7.10 Equivalency terms 157
7.11 Food and Drug Administration codes 157
7.12 Fallacies on bioequivalence 158
7.13 Evidence of generic bioinequivalence or of therapeutic inequivalence for certain formulations approved by the FDA 159
Problem set 3 161
8 Factors affecting drug absorption: Physicochemical factors 175
8.1 Dissolution rate 175
8.2 Dissolution process 175
8.3 Noyes-Whitney equation and drug dissolution 176
8.4 Factors affecting the dissolution rate 177
9 Gastrointestinal absorption: Role of the dosage form 187
9.1 Introduction 187
9.2 Solution (elixir, syrup, and solution) as a dosage form 188
9.3 Suspension as a dosage form 188
9.4 Capsule as a dosage form 189
9.5 Tablet as a dosage form 189
9.6 Dissolution methods 191
9.7 Formulation and processing factors 191
9.8 Correlation of in vivo data with in vitro dissolution data 194
10 Continuous intravenous infusion (one-compartment model) 203
10.1 Introduction 203
10.2 Monitoring drug in the body or blood (plasma/serum) 205
10.3 Sampling drug in body or blood during infusion 205
10.4 Sampling blood following cessation of infusion 220
10.5 Use of post-infusion plasma concentration data to obtain half life, elimination rate constant and the apparent volume of distribution 222
10.6 Rowland and Tozer method 225
Problem set 4 227
11 Multiple dosing: Intravenous bolus administration 237
11.1 Introduction 237
11.2 Useful pharmacokinetic parameters in multiple dosing 241
11.3 Designing or establishing the dosage regimen for a drug 248
11.4 Concept of drug accumulation in the body (R) 249
11.5 Determination of fluctuation (Φ): intravenous bolus administration 251
11.6 Number of doses required to reach a fraction of the steady-state condition 254
11.7 Calculation of loading and maintenance doses 254
11.8 Maximum and minimum drug concentration at steady state 255
12 Multiple dosing: extravascular routes of drug administration 257
12.1 Introduction 257
12.2 The peak time in multiple dosing to steady state (t′max) 259
12.3 Maximum plasma concentration at steady state 260
12.4 Minimum plasma concentration at steady state 261
12.5 "Average" plasma concentration at steady state: extravascular route 262
12.6 Determination of drug accumulation: extravascular route 263
12.7 Calculation of fluctuation factor (Φ) for multiple extravascular dosing 264
12.8 Number of doses required to reach a fraction of steady state: extravascular route 264
12.9 Determination of loading and maintenance dose: extravascular route 265
12.10 Interconversion between loading, maintenance, oral, and intravenous bolus doses 266
Problem set 5 271
13 Two-compartment model 285
13.1 Introduction 285
13.2 Intravenous bolus administration: two-compartment model 287
13.3 Determination of the post-distribution rate constant (β) and the coefficient B 292
13.4 Determination of the distribution rate constant (α) and the coefficient A 292
13.5 Determination of micro rate constants: the inter-compartmental rate constants (K21 and K12) and the pure elimination rate constant (K10) 295
13.6 Determination of volumes of distribution (V) 296
13.7 How to obtain the area under the plasma concentration-time curve from time zero to time t and time ∞ 298
13.8 General comments 299
13.9 Example 300
13.10 Further calculations to perform and determine the answers 302
13.11 Extravascular dosing of a two-compartment model drug 303
Problem set 6 305
14 Multiple intermittent infusions 309
14.1 Introduction 309
14.2 Drug concentration guidelines 311
14.3 Example: determination of a multiple intermittent infusion dosing regimen for an aminoglycoside antibiotic 311
14.4 Does to the patient from a multiple intermittent infusion 313
14.5 Multiple intermittent infusion of a two-compartment drug: vancomycin "peak" at 1 hour post infustion 313
14.6 Vancomycin dosing regimen problem 314
14.7 Adjustment for early or late drug concentrations 315
Problem set 7 319
15 Nonlinear pharmacokinetics 323
15.1 Introduction 323
15.2 Capacity-limited metabolism 325
15.3 Estimation of Michaelis-Menten parameters (Vmax and Km) 327
15.4 Relationship between the area under the plasma concentration versus time curve and the administered dose 330
15.5 Time to reach a given fraction of steady state 332
15.6 Example: calculation of parameters for phenytoin 333
Problem set 8 337
16 Drug interactions 341
16.1 Introduction 341
16.2 The effect of protein-binding interactions 342
16.3 The effect of tissue-binding interactions 348
16.4 Cytochrome P450-based drug interactions 349
16.5 Drug interactions linked to transporters 355
Problem set 9 357
17 Pharmacokinetic and pharmacodynamic relationships 359
17.1 Introduction 359
17.2 Generation of a pharmacokinetic- pharmacodynamic (PKPD) equation 361
17.3 Pharmacokinetic and pharmacodynamic drug interactions 364
Problem set 10 367
18 Metabolite pharmacokinetics 369
18.1 Introduction 369
18.2 General model 370
18.3 Single intravenous bolus of drug conforming to a one-compartment model 370
18.4 Single oral dose of drug conforming to a one-compartment model 382
18.5 Intravenous infusion of a one-compartment model parent drug 384
18.6 Chronic dosing to steady state 385
18.7 Study design required to obtain various metabolite pharmacokinetic parameters 388
18.8 Computer-aided simulation and fitting of metabolite pharmacokinetic data 388
18.9 Case in point: meperidine and normeperidine 388
18.10 Active metabolites in renal dysfunction 388
18.11 Sample metabolite pharmacokinetics calculations 393
19 Pharmacokinetic data fitting 395
19.1 Introduction 395
19.2 Pharmacokinetic parameter determination 395
19.3 Nonlinear regression 397
19.4 Goodness of fit indices 398
19.5 Ways to improve fit 401
19.6 Evaluation of program output 401
19.7 How are the values of the parameters determined? 404
19.8 Problems that may occur during a nonlinear regression run 407
19.9 Weighting of data points 408
19.10 Simulation 409
19.11 Initial estimates 411
19.12 Conclusion 412
20 Pharmacokinetics and pharmacodynamics of biotechnology drugs 413
20.1 Introduction 413
20.2 Proteins and peptides 413
20.3 Monoclonal antibodies 419
20.4 Oligonucleotides 423
20.5 Vaccines (immunotherapy) 424
20.6 Gene therapies 425
Appendix: Statistical moment theory in pharmacokinetics 427
A1 Introduction 427
A2 Statistical moment theory 428
A3 Applications 439
Glossary 443
References 453